There are numerous types of nucleic acid carriers that can be used to deliver genetic material inside cells. Transfection can be achieved using viral methods (ex: viruses, bacteriophages), physical methods (ex: electroporation, lasers, heat, injected nanoparticles) or through chemical based methods such as combining DNA with nanoparticles, cyclodetrins, liposomes, dendrimers or polymers that are then encapsulated by target cells. Polyelectrolyte complexes of nucleic acids with polycations (polyplexes) can be used for delivery of nucleic acids.
The main benefits of bioreducible polycation polymers (BRP) are reduced toxicity and, compared to hydrolytically degradable polycations, better spatial control of disassembly and release of DNA that is localized predominantly to the cytoplasm and nucleus. Improved spatial control of polyplex disassembly has been shown to enhance transfection of several types of nucleic acids (plasmid DNA, mRNA, siRNA) in a number of cancer cell lines. Bioreducible polycations are degraded selectively in the reducing intracellular space. The CXCR4 receptor is expressed on multiple cell types including lymphocytes, hematopoietic stem cells, endothelial and epithelial cells and cancer cells. CXCR4 is a trans-membrane chemokine receptor protein specific for a ligand known as CXCL12. Therapeutics that can act as antagonists and inhibit or block the CXCR4/CXCL12 pathway are important drug targets. Incorporation of known CXCR4 inhibiting moieties into carriers should allow targeting of cells expressing CXCR4. Cyclam compound derivatives that act as CXCR4 inhibitors have been developed, notably the AIDS drug AMD-3100. In addition cyclam derivatives form highly stable complexes with virtually all transition metal ions, particularly, cyclam (1,4,8,11-tetraazacyclotetradecane) a well-known macrocyclic ligand.
While there are many classes of BRP known, a need still exists for polymers that can act as CXCR4 inhibitors. Bioreducible polymers that are suitable for applications where biodegradability is required (i.e., systemic delivery of nucleic acids) and can simultaneously act as CXCR4 inhibitors present a promising dual function approach.